Melanoma can metastasize at an early stage, and these metastases are typically resistant to medical treatment. In addition, melanoma is rising in incidence and mortality, greatly increasing the need for methods of prevention, early diagnosis, and treatment. Primary human cutaneous melanoma often has activating mutations in either NRAS or BRAF early in its progression; these activating mutations likely have a causal rather than simply correlative role in melanoma development; and evidence exists to support ultraviolet, in combination with genotypic and associated phenotypic susceptibilities, in the pathogenesis of somatic mutations in melanoma. We propose to determine the population-based frequencies of NRAS and BRAF somatic mutations in melanomas in a large international cohort and their associations with histologic subtypes, known risk factors, and prognostic indicators in melanoma. In addition, we will determine whether tumors from patients with second primary melanoma exhibit similar molecular classifications to the first primary. NRAS and BRAF mutational status will be characterized using a highly sensitive combination of laser capture microscopy and single strand conformational polymorphism analysis with direct manual sequencing of PCR products. Understanding of the role of these somatic mutations in the etiology and progression of melanoma likely will be crucial for its prevention, improved diagnosis, and effective application of new clinical treatments.